[PPT] - 1 AD pathology is more likely to be clinically 20% more women than PowerPoint Presentation

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Sex Differences in Alzheimer’s Disease

Pauline M. Maki, Ph.D. Pauline M. Maki, Ph.D. Professor of Psychiatry and Psychology Professor of Psychiatry and Psychology University of Illinois at Chicago University of Illinois at Chicago

travel support from Abbott
consultant for Pfizer, Bayer, & Noven

R h f di f NIH

Disclosures Disclosures

Research funding from NIH

#MH083782, #HD055892, #AI082151, and #AI034993.

Objectives Objectives

1. Describe sex differences in the prevalence and

incidence of Alzheimer’s Disease

2. Understand how reproductive aging and hormone

therapy might influence the risk for AD

1. Describe sex differences in the prevalence and

incidence of Alzheimer’s Disease

2. Understand how reproductive aging and hormone

therapy might influence the risk for AD therapy might influence the risk for AD

3. Describe sex differences in risk factors for AD.

therapy might influence the risk for AD

3. Describe sex differences in risk factors for AD.

Objectives Objectives

1. Describe sex differences in the prevalence and

incidence of Alzheimer’s Disease

2. Understand how reproductive aging and hormone

therapy might influence the risk for AD

1. Describe sex differences in the prevalence and

incidence of Alzheimer’s Disease

2. Understand how reproductive aging and hormone

therapy might influence the risk for AD therapy might influence the risk for AD

3. Describe sex differences in risk factors for AD.

therapy might influence the risk for AD

3. Describe sex differences in risk factors for AD.

Age Age-

adjusted death rates for selected leading causes

adjusted death rates for selected leading causes

f death: United States, 1958
f death: United States, 1958-
2005

2005

1,000.0 100.0 U.S. standard ion ICD-7 ICD-8 ICD-9 Nephritis, nephrotic Malignant neoplasms Accidents Cerebrovascular diseases Heart disease 2 3 5 1 ICD-10 1 Circled numbers indicate ranking of conditions as leading causes of death in 2005. 1.0 1980 1970 10.0 1975 1960 1990 1985 1995 1965 0.1 Rate per 100,000 U populat p , p syndrome and nephrosis 7 Alzheimer’s disease 13 1958 2000 Hypertension Parkinson’s disease 9 14 2005 Source: CDC National Vital Statistics Report, Source: CDC National Vital Statistics Report, Kung et al. Deaths: Final Data for 2005; Vol 56, No 10, 2008 Source: CDC National Vital Statistics Report, Source: CDC National Vital Statistics Report, Kung et al. Deaths: Final Data for 2005; Vol 56, No 10, 2008

Sex differences in top 10 causes of death Sex differences in top 10 causes of death in in the U.S. the U.S.

1.5 2 2.5

Heart disease Malignant neoplasms Cerebrovascular diseases Chronic lower respiratory diseases

0.5 1 1.5 Male: Female Ratio

Accidents Diabetes mellitus Alzheimer's disease Influenza and pneumonia Nephritis, nephrotic syndrome and nephrosis Septicemia Source: CDC National Vital Statistics Report, Source: CDC National Vital Statistics Report, Kung et al. Deaths: Final Data for 2005; Vol 56, No 10, 2008 Source: CDC National Vital Statistics Report, Source: CDC National Vital Statistics Report, Kung et al. Deaths: Final Data for 2005; Vol 56, No 10, 2008

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EURODEM: A 65 EURODEM: A 65-

year

year-

old woman has a greater
ld woman has a greater

risk of AD compared to a man risk of AD compared to a man

Women Men

Andersen, K et al. Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. Andersen, K et al. Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. Neurology

Neurology. 53(9):1992

. 53(9):1992-

1997, December 10, 1999.

1997, December 10, 1999.

20% more women than men die of Alzheimer’s 20% more women than men die of Alzheimer’s even after adjusting for age (longevity) even after adjusting for age (longevity)

per 100,000

Moschetti Moschetti et al., 1999 et al., 1999-

2008.
2008. JAGS

JAGS 2012 Aug;60(8):1509 2012 Aug;60(8):1509-

14. Burden of Alzheimer's disease
14. Burden of Alzheimer's disease-
related mortality in the

related mortality in the United States United States

Mortality Rate

AD pathology is more likely to be clinically expressed as dementia in women

Barnes, L et al. Barnes, L et al. Sex Differences in the Clinical Manifestations of Alzheimer Disease Pathology. . Arch Gen Psychiatry. 2005;62(6):685-691. . .

Paradoxically, risk of MCI is higher in men

Petersen, RC et al. Petersen, RC et al. The incidence of MCI differs by subtype and is higher in men: the Mayo Clinic Study of Aging.

Neurology. 2012 Jan 31;78(5):342-51.

AD/MCI Paradox

Rate of MCI higher in men, but rate of AD

higher in women.

Women might transition from normal

cognition directly to dementia at a later

Petersen, RC et al. Petersen, RC et al. The incidence of MCI differs by subtype and is higher in men: the Mayo Clinic Study of Aging.

Neurology. 2012 Jan 31;78(5):342-51.

cognition directly to dementia at a later age but might transition more abruptly.

Greater cognitive deterioration in women than men with Alzheimer's: A meta analysis

Male Advantage

Semantic Nonsemantic Verbal

Female Advantage Cognitive Domain Effect Size (95% CI)

1.0
0.50
0.25

0.25

Adapted from Irvine, et al. Adapted from Irvine, et al. Greater cognitive deterioration in women than men with Alzheimer's disease: A meta analysis JCEN

JCEN. 2012;

. 2012; 2012;34(9):989-98. .

Verbal Visuospatial Memory

0.75

0.50 0.75

Note. A negative effect size (Hedges’s d) denotes a male advantage and a positive effect

size a female advantage.

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Objectives Objectives

1. Describe sex differences in the prevalence and

incidence of Alzheimer’s Disease

2. Understand how reproductive aging and hormone

therapy might influence the risk for AD

1. Describe sex differences in the prevalence and

incidence of Alzheimer’s Disease

2. Understand how reproductive aging and hormone

therapy might influence the risk for AD therapy might influence the risk for AD

3. Describe sex differences in risk factors for AD.

therapy might influence the risk for AD

3. Describe sex differences in risk factors for AD.

Women Women-

specific risk factors for AD

specific risk factors for AD

Menopause and menopausal symptoms

Hysterectomy and oopherectomy (removal of uterus and ovaries) Use of hormone therapy

Other hormone treatments Menopause and menopausal symptoms

Hysterectomy and oopherectomy (removal of uterus and ovaries) Use of hormone therapy

Other hormone treatments Other hormone treatments

Osteoporosis Breast cancer

Other hormone treatments

Osteoporosis Breast cancer

Uncertainty about hormone therapy and Uncertainty about hormone therapy and risk for AD risk for AD

Risk factor for AD? Protective against AD? Neutral? Risk factor for AD? Protective against AD? Neutral? Depends on conditions – age, health? Depends on conditions – age, health?

Critical Window Hypothesis Critical Window Hypothesis

The neuroprotective effects of hormone therapy

depend on timing of initiation in relation to the menopause and/or age

Initiation of hormone therapy early in the The neuroprotective effects of hormone therapy

depend on timing of initiation in relation to the menopause and/or age

Initiation of hormone therapy early in the

menopausal transition is associated with cognitive benefit but later initiation confers no cognitive benefit menopausal transition is associated with cognitive benefit but later initiation confers no cognitive benefit Observational Studies Show a Decreased Risk Observational Studies Show a Decreased Risk

f AD in Hormone Therapy Users
f AD in Hormone Therapy Users

Retrospective Prospective

Heyman et al, 1984 Amaducci et al, 1986 Broe et al, 1990 Graves et al, 1990 Brenner et al, 1994 Henderson et al, 1994 Mortel & Meyer, 1995 Paganini-Hill & Henderson, 1996

Relative Risk (95% CI)

1 2 3 4

Prospective Meta-Analysis

*Confidence interval not provided. Adapted from LeBlanc ES, et al. JAMA. 2001;285:1489-1499. Baldereschi et al, 1998 Waring et al, 1999 Slooter et al, 1999 Seshadri et al, 2001 Tang et al, 1996 Kawas et al, 1997 Zandi et al, 2002 Shumaker SA, et al. 2003 Yaffe et al, 1998 Hogervorst et al, 2000 LeBlanc et al, 2001 * *

Women’s Health Initiative Memory Study Women’s Health Initiative Memory Study

Shumaker SA, et al. JAMA. 2004;291:2947-58.

CEE Alone (n = 1464) Placebo (n = 1483) HR (95% CI) Cases of probable dementia† 28 19 1.49 (0.83–2.66) Rate per 10,000 person-years 37 25

†Mean follow-up in CEE alone vs placebo arms: 5.21 ± 1.73 years.

CEE+MPA (n = 2229) Placebo (n = 2303) HR (95% CI) Cases of probable dementia* 40 21 2.05 (1.21–3.48) Rate per 10,000 person-years 45 22

*Mean follow-up in CEE+MPA vs placebo arms: 4.05 ± 1.19 years. Shumaker SA, et al. JAMA. 2003;289:2651-62.

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HT: timing of initiation based

n proximity to menopause,

Cache County, Utah

within 5 years of menopause 5+ years after menopause

Observational Studies of HT and AD Observational Studies of HT and AD prevention: Evidence for the Critical Window prevention: Evidence for the Critical Window Observational Studies of HT and AD Observational Studies of HT and AD prevention: Evidence for the Critical Window prevention: Evidence for the Critical Window

Slide courtesy of Victor Henderson

1.0 3.0 0.5 0.1 2.0 Shao et al., Neurology 2012, 79:1846; Whitmer et al., Ann. Neurol. 2011;69:163; Henderson et al., J. Neurol. Neurosurg. Psychiatry 2005;76:103.

late-life only midlife only midlife + late-life

HT: timing of use based on midlife or late-life use, Kaiser Permenante

youngest age tertile middle

ldest

HT: timing based on age, MIRAGE (Multi-

Institutional Research in Alzheimer’s Genetic Epidemiology)

30 40

nce (%) Oophorectomy Oophorectomy ≤ 48 y

Mayo Clinic Cohort Study of

Oophorectomy and Aging

Use of estrogen therapy until age 50

removed that risk

Removal of ovaries before age Removal of ovaries before age 48 increases 48 increases risk of AD by risk of AD by 70 70% %

Rocca WA et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before

menopause. Neurology 2007;69:1074-1083.

Rocca WA et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before

menopause. Neurology 2007;69:1074-1083.

10 20 40 50 60 70 80

Age (years) Inciden y > 48 y Other women

Evidence that Evidence that raloxifene raloxifene can can lower the risk lower the risk

f preclinical AD
f preclinical AD
Raloxifene (a drug to treat osteoporosis)

Raloxifene (a drug to treat osteoporosis)

Acts like estrogen in some tissue and

Acts like estrogen in some tissue and blocks estrogen in other tissue blocks estrogen in other tissue

Randomized clinical trial of 5,386 women

Randomized clinical trial of 5,386 women aged 66 years on average aged 66 years on average

Yaffe K, et al. Am J Psychiatry. 2005;162:683-90.

aged 66 years on average aged 66 years on average

60 mg dose

60 mg dose

120 mg dose

120 mg dose

After 3 years, 120 mg dose decreased risk

After 3 years, 120 mg dose decreased risk

f preclinical AD by 33%
f preclinical AD by 33%

Objectives Objectives

1. Describe sex differences in the prevalence and

incidence of Alzheimer’s Disease

2. Understand how reproductive aging and hormone

therapy might influence the risk for AD

1. Describe sex differences in the prevalence and

incidence of Alzheimer’s Disease

2. Understand how reproductive aging and hormone

therapy might influence the risk for AD therapy might influence the risk for AD

3. Describe sex differences in risk factors for AD.

therapy might influence the risk for AD

3. Describe sex differences in risk factors for AD.

Sex differences in risk factors for AD Sex differences in risk factors for AD

Compared to men, women have:

Higher rates of depression Lower rates of exercise Greater risk due to the predominant genetic risk

Compared to men, women have:

Higher rates of depression Lower rates of exercise Greater risk due to the predominant genetic risk Greater risk due to the predominant genetic risk

factor (ApoE4)

Sex-specific risk due to another genetic risk

factor (Val66met)

Greater risk due to the predominant genetic risk

factor (ApoE4)

Sex-specific risk due to another genetic risk

factor (Val66met)

Women have a greater risk of depression, Women have a greater risk of depression, a a risk for AD risk for AD

Depression 1.9x increased risk of AD1
Women 1.7x increased risk of depression2

1 Ownby Ownby et al. Arch Gen Psychiatry. 2006 May;63(5):530 et al. Arch Gen Psychiatry. 2006 May;63(5):530-

8.

8. 2 Kessler et al. J Affect Kessler et al. J Affect Disord

Disord. 1993 Oct

. 1993 Oct-

Nov;29(2

Nov;29(2-

3):85

3):85-

96.

96.

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Women Women exercise less than men exercise less than men

N = 13,838, aged 18-65 from National Health

Interview Survey

Average 5 hrs exercise in 2-wk period

Women: 4hr 17m Men: 5hr 43m

N = 13,838, aged 18-65 from National Health

Interview Survey

Average 5 hrs exercise in 2-wk period

Women: 4hr 17m Men: 5hr 43m Men: 5hr 43m

Family roles are related to less time exercising

for men and women

variations by work and family roles are greater for men than for women (marriage affects exercise time more in men than in women). Motherhood is a factor only if children < 5 y Men: 5hr 43m

Family roles are related to less time exercising

for men and women

variations by work and family roles are greater for men than for women (marriage affects exercise time more in men than in women). Motherhood is a factor only if children < 5 y

Nomaguchi Nomaguchi, K. M., & Bianchi, S. M. (2004). Exercise time: Gender differences in the effects of marriage, parenthood, , K. M., & Bianchi, S. M. (2004). Exercise time: Gender differences in the effects of marriage, parenthood, and employment. Journal of Marriage and Family, 66, 413 and employment. Journal of Marriage and Family, 66, 413-

430.

430.

Body Mass Index (BMI) > 30 doubles risk Body Mass Index (BMI) > 30 doubles risk

f dementia 21 years later
f dementia 21 years later

Body Mass Index (BMI) > 30 doubles risk Body Mass Index (BMI) > 30 doubles risk

f dementia 21 years later
f dementia 21 years later

18 19 21 23 26 18 19 21 23 26 30 34 39 45 30 34 39 45

Kivipelto, M. et al. Arch Neurol 2005;62:1556-1560; Bulik et al.,Int J Obes Relat Metab Disord, 2001;25:1517-24 Kivipelto, M. et al. Arch Neurol 2005;62:1556-1560; Bulik et al.,Int J Obes Relat Metab Disord, 2001;25:1517-24

Exercise at midlife reduces Alzheimer’s Exercise at midlife reduces Alzheimer’s risk later in life risk later in life

Leisure time physical

activity at midlife (50 years) at least twice per week decreased

Leisure time physical

activity at midlife (50 years) at least twice per week decreased AD by 62%

True even for those

with genetic risk factor for AD AD by 62%

True even for those

with genetic risk factor for AD

Rovio et al., Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease, Lancet Neurol 4 (2005), pp. 705–711. Rovio et al., Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease, Lancet Neurol 4 (2005), pp. 705–711.

Sex differences in genetic risk factors Sex differences in genetic risk factors for AD for AD

Most prominent genetic risk factor for AD,

Most prominent genetic risk factor for AD, ApoE4, has a greater impact in women than ApoE4, has a greater impact in women than men men1

1.5 times higher risk in carriers of risk factor (~24%

f population;
f population; APOE3/4

APOE3/4) compared to those without ) compared to those without the risk factor (~63% of population; the risk factor (~63% of population; APOE3/3 APOE3/3) ( p p ( p p )

Another genetic risk factor, val66met, is a risk

Another genetic risk factor, val66met, is a risk factor only in women factor only in women2

AD risk was 14% higher among women with the risk

AD risk was 14% higher among women with the risk factor factor

1 1 Farrer Farrer LA, et al. LA, et al. JAMA. 1997 Oct 22

JAMA. 1997 Oct 22-
29;278(16):1349

29;278(16):1349-

56.

56. 2 2 Fukumoto Fukumoto et al. et al. American Journal of Medical Genetics . 2010 Jan;153b(1):235 American Journal of Medical Genetics . 2010 Jan;153b(1):235-

242.

242.

Low Education is a Risk Factor for Low Education is a Risk Factor for Alzheimer’s: Especially for Women? Alzheimer’s: Especially for Women?

Among individuals over age 65 today,

educational levels are lower in women

Low education is associated with an increased

risk for Alzheimer’s disease1, 2

Among individuals over age 65 today,

educational levels are lower in women

Low education is associated with an increased

risk for Alzheimer’s disease1, 2

Does not explain the sex difference in AD2 Does not explain the sex difference in AD2

1 1 Lettenneur Lettenneur, et al. , et al. Education and the risk for Alzheimer's disease: sex makes a difference. EURODEM pooled

analyses. EURODEM Incidence Research Group. Am J Epidemiol. 2000 Jun 1;151(11):1064-71.

2 Lettenneur, et al. Are sex and educational level independent predictors of dementia and Alzheimer’s disease? Incidence data from the PAQUID project. J Neurol Neurosurg Psychiatry. 1999;66:177-183.

Summary Summary

More women than men will die of AD Sex differences in risk factors for AD

Menopause, Hormone Therapy, and SERMs D i

More women than men will die of AD Sex differences in risk factors for AD

Menopause, Hormone Therapy, and SERMs D i Depression Exercise Genetics Education Depression Exercise Genetics Education

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Women’s Mental Health Research Program Women’s Mental Health Research Program